Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Stat3 regulates genes common to both wound healing and cancer

Abstract

Wound healing and cancer are both characterized by cell proliferation, remodeling of extracellular matrix, cell invasion and migration, new blood vessel formation, and modulation of blood coagulation. The mechanisms that link wound healing and cancer are poorly understood. We report here that Stat3, a common signaling mechanism involved in oncogenesis and tissue injury, regulates a common set of genes involved in wound healing and cancer. Using oligonucleotide gene arrays and quantitative real-time PCR, we evaluated changes in global gene expression resulting from expression of Stat3 in lung epithelial cells. We report here previously uncharacterized genes induced by Stat3 implicated in signaling pathways common to both wound healing and cancer including cell invasion and migration, angiogenesis, modulation of coagulation, and repression of interferon-inducible genes. Consistent with these results, we found increased Stat3 activity associated with wound healing in chronically inflamed mouse lungs and increased Stat3 activity was identified at the leading edge of lung tumors invading adjacent nontumor stroma. These findings provide a molecular basis for understanding cancer as a deregulation of normal wound healing processes.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  • Bauer AK, Dwyer-Nield LD, Hankin JA, Murphy RC and Malkinson AM . (2001a). Toxicology, 169, 1–15.

  • Bauer AK, Dwyer-Nield LD, Keil K, Koski K and Malkinson AM . (2001b). Exp. Lung Res., 27, 197–216.

  • Bolstad BM, Irizarry RA, Astrand M and Speed TP . (2003). Bioinformatics, 19, 185–193.

  • Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA and Jove R . (2001). Proc. Natl. Acad. Sci. USA, 98, 7319–7324.

  • Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J and Vingron M . (2001). Nat. Genet., 29, 365–371.

  • Bromberg JF, Horvath CM, Wen Z, Schreiber RD and Darnell Jr JE . (1996). Proc. Natl. Acad. Sci. USA, 93, 7673–7678.

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C and Darnell JE . (1999). Cell, 98, 295–303.

  • Chan KS, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J and DiGiovanni J . (2004). J. Clin. Invest., 114, 720–728.

  • Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, Rijn Mv M, Botstein D and Brown PO . (2004). PloS. Biol., 2, E7.

  • Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH and Borden EC . (2003). Apoptosis, 8, 237–249.

  • Christensen PJ, Du M, Moore B, Morris S, Toews GB and Paine III R . (2004). Am. J. Physiol. Lung Cell Mol. Physiol., 286, L68–L72.

  • Costa-Pereira AP, Tininini S, Strobl B, Alonzi T, Schlaak JF, Is'harc H, Gesualdo I, Newman SJ, Kerr IM and Poli V . (2002). Proc. Natl. Acad. Sci. USA, 99, 8043–8047.

  • Coussens LM and Werb Z . (2002). Nature, 420, 860–867.

  • Duan HO and Simpson-Haidaris PJ . (2003). J. Biol. Chem., 278, 41270–41281.

  • Dvorak HF . (1986). N. Engl. J. Med., 315, 1650–1659.

  • Epperly MW, Epstein CJ, Travis EL and Greenberger JS . (2000). Radiat. Res., 154, 365–374.

  • Fujitani Y, Nakajima K, Kojima H, Nakae K, Takeda T and Hirano T . (1994). Biochem. Biophys. Res. Commun., 202, 1181–1187.

  • Gao H, Guo RF, Speyer CL, Reuben J, Neff TA, Hoesel LM, Riedemann NC, McClintock SD, Sarma JV, Van Rooijen N, Zetoune FS and Ward PA . (2004). J. Immunol., 172, 7703–7712.

  • Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y and Kim JD . (2000). Proc. Natl. Acad. Sci. USA, 97, 4227–4232.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • He B, You L, Uematsu K, Matsangou M, Xu Z, He M, McCormick F and Jablons DM . (2003). Biochem. Biophys. Res. Commun., 301, 386–391.

  • He TC, Zhou S, da Costa LT, Yu J, Kinzler KW and Vogelstein B . (1998). Proc. Natl. Acad. Sci. USA, 95, 2509–2514.

  • Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl AK, Hull WM, Wert SE and Whitsett JA . (2004). J. Clin. Invest., 113, 28–37.

  • Hur GC, Cho SJ, Kim CH, Kim MK, Bae SI, Nam SY, Park JW, Kim WH and Lee BL . (2003). Clin. Cancer Res., 9, 5768–5775.

  • Hutt JA, O'Rourke JP and DeWille J . (2000). J. Biol. Chem., 275, 29123–29131.

  • Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B and Speed TP . (2003a). Nucleic. Acids Res., 31, e15.

  • Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U and Speed TP . (2003b). Biostatistics, 4, 249–264.

  • Kano A, Wolfgang MJ, Gao Q, Jacoby J, Chai GX, Hansen W, Iwamoto Y, Pober JS, Flavell RA and Fu XY . (2003). J. Exp. Med., 198, 1517–1525.

  • Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ and Schreiber RD . (1998). Proc. Natl. Acad. Sci. USA, 95, 7556–7561.

  • Khatri P, Bhavsar P, Bawa G and Draghici S . (2004). Nucleic. Acids Res., 32, W449–W456.

  • Khatri P, Draghici S, Ostermeier GC and Krawetz SA . (2002). Genomics, 79, 266–270.

  • Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ and Tainsky MA . (2003). Oncogene, 22, 4118–4127.

  • Lakka SS, Rajagopal R, Rajan MK, Mohan PM, Adachi Y, Dinh DH, Olivero WC, Gujrati M, Ali-Osman F, Roth JA, Yung WK, Kyritsis AP and Rao JS . (2001). Clin. Cancer Res., 7, 1087–1093.

  • Levy DE and Darnell Jr JE . (2002). Nat. Rev. Mol. Cell. Biol., 3, 651–662.

  • Lieber M, Smith B, Szakal A, Nelson-Rees W and Todaro G . (1976). Int. J. Cancer, 17, 62–70.

  • Mora LB, Buettner R, Seigne J, Diaz J, Ahmad N, Garcia R, Bowman T, Falcone R, Fairclough R, Cantor A, Muro-Cacho C, Livingston S, Karras J, Pow-Sang J and Jove R . (2002). Cancer Res., 62, 6659–6666.

  • Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R and Yu H . (2002). Oncogene, 21, 2000–2008.

  • Palumbo JS, Kombrinck KW, Drew AF, Grimes TS, Kiser JH, Degen JL and Bugge TH . (2000). Blood, 96, 3302–3309.

  • Palumbo JS, Potter JM, Kaplan LS, Talmage K, Jackson DG and Degen JL . (2002). Cancer Res., 62, 6966–6972.

  • Rao JS . (2003). Nat. Rev. Cancer, 3, 489–501.

  • Reiland J, Furcht LT and McCarthy JB . (1999). Prostate, 41, 78–88.

  • Reljic R, Wagner SD, Peakman LJ and Fearon DT . (2000). J. Exp. Med., 192, 1841–1848.

  • Romer J, Lund LR, Eriksen J, Pyke C, Kristensen P and Dano K . (1994). J. Invest. Dermatol., 102, 519–522.

  • Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, Yoshikawa K, Akira S and Takeda J . (1999). EMBO J., 18, 4657–4668.

  • Saunders NA, Smith RJ and Jetten AM . (1994). Am. J. Resp. Cell Mol. Biol., 11, 147–152.

  • Schumann RR, Kirschning CJ, Unbehaun A, Aberle HP, Knope HP, Lamping N, Ulevitch RJ and Herrmann F . (1996). Mol. Cell. Biol., 16, 3490–3503.

  • Severgnini M, Takahashi S, Rozo LM, Homer RJ, Kuhn C, Jhung JW, Perides G, Steer M, Hassoun PM, Fanburg BL, Cochran BH and Simon AR . (2004). Am. J. Physiol. Lung. Cell Mol. Physiol., 286, L1282–L1292.

  • Shou J, Soriano R, Hayward SW, Cunha GR, Williams PM and Gao WQ . (2002). Proc. Natl. Acad. Sci. USA, 99, 2830–2835.

  • Song L, Turkson J, Karras JG, Jove R and Haura EB . (2003). Oncogene, 22, 4150–4165.

  • Steinman RA, Wentzel A, Lu Y, Stehle C and Grandis JR . (2003). Oncogene, 22, 3608–3615.

  • Sue RD, Belperio JA, Burdick MD, Murray LA, Xue YY, Dy MC, Kwon JJ, Keane MP and Strieter RM . (2004). J. Immunol., 172, 3860–3868.

  • Tusher VG, Tibshirani R and Chu G . (2001). Proc. Natl. Acad. Sci. USA, 98, 5116–5121.

  • Van Gelder RN, von Zastrow ME, Yool A, Dement WC, Barchas JD and Eberwine JH . (1990). Proc. Natl. Acad. Sci. USA, 87, 1663–1667.

  • Vultur A, Cao J, Arulanandam R, Turkson J, Jove R, Greer P, Craig A, Elliott B and Raptis L . (2004). Oncogene, 23, 2600–2616.

  • Wakabayashi H, Cavanaugh PG and Nicolson GL . (1995). Cancer Res., 55, 4458–4464.

  • Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, Bhattacharya R, Gabrilovich D, Heller R, Coppola D, Dalton W, Jove R, Pardoll D and Yu H . (2004). Nat. Med., 10, 48–54.

  • Warrington JA, Nair A, Mahadevappa M and Tsyganskaya M . (2000). Physiol. Genomics, 2, 143–147.

  • Yan H, Dobbie Z, Gruber SB, Markowitz S, Romans K, Giardiello FM, Kinzler KW and Vogelstein B . (2002). Nat. Genet., 30, 25–26.

  • Yu H and Jove R . (2004). Nat. Rev. Cancer, 4, 97–105.

Download references

Acknowledgements

We thank Dr Robert Engleman for assistance with pathological examination of the mouse tissues and Dr Steven Eschrich for review of the microarray analysis. We thank Dr Jacqueline Bromberg for providing Stat3C. We thank Gerold Bepler for critical review of the manuscript, Zhao Chen for statistical advice, and Rebecca Alexander for administrative assistance. This work has been supported in part by the Molecular Imaging Core, Molecular Biology and Sequencing Core, and the DNA Microarray Core at the H Lee Moffitt Cancer Center & Research Institute. This work was partially funded by the Chiles Endowment Biomedical Research Program of the Florida Department of Health (EBH), by a Department of Defense National Functional Genomics Grant (RJ), and by the H Lee Moffitt Cancer Center.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric B Haura.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dauer, D., Ferraro, B., Song, L. et al. Stat3 regulates genes common to both wound healing and cancer. Oncogene 24, 3397–3408 (2005). https://doi.org/10.1038/sj.onc.1208469

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208469

Keywords

  • STAT proteins
  • cancer
  • wound healing
  • Stat3
  • lung cancer

Further reading

Search

Quick links